Morpholine derivatives, compositions containing them and their use as therapeutic agents

ABSTRACT

The present invention relates to compounds of formula (I), wherein R 1  and R 4  represent hydrogen, halogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4  alkyl, C 1-6  alkoxy, C 1-4  alkyl substituted by a hydroxy or C 1-4  alkoxy group, OCF 3 , hydroxy, trifluoromethyl, trimethylsilyl, nitro, CN, SR a , SOR a , SO 2  R a , COR a , CO 2  R a  or CONR a  R b , where R a  and R b  are each independently hydrogen or C 1-4  alkyl; R 2 , R 3  and R 5  represent hydrogen, halogen, C 1-6  alkyl, C 1-4  alkoxy substituted by a C 1-4  alkoxy group, or trifluoromethyl; R 6  represents C 1-6  alkyl, optionally substituted by oxo, substituted by a 5-membered heteroaromatic ring selected from oxazole, thiazole, isoxazole, isothiazole, oxadiazole and thiadiazole, wherein each heteroaromatic ring is substituted at the available carbon atom by a group of the formula: ZNR 7  R 8 . The compounds are of particular use in the treatment of pain, inflammation, migraine and emesis.

This application is a 371 of PCT/GB96/00587 filed Mar. 13, 1996,published as WO96/29328 Sep. 26, 1996.

This invention relates to a class of morpholine compounds which areuseful as tachykinin antagonists. More particularly, the compounds ofthe invention are N-substituted morpholine derivatives bearing aheteroaromatic moiety.

The tachykinins are a group of naturally occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in peripheral nervous and circulatory systems.

At present, there are three known mammalian tachykinins referred to assubstance P, neurokinin A (NKA, substance K, neuromedin L) andneurokinin B (NKB, neuromedin K) (for review see J. E. Maggio, Peptides(1985) 6(suppl. 3), 237-242). The current nomenclature designates thethree tachykinin receptors mediating the biological actions of substanceP, NKA and NKB as the NK₁, NK₂ and NK₃ receptors, respectively.

Evidence for the usefulness of tachykinin receptor antagonists in pain,headache, especially migraine, Alzheimer's disease, multiple sclerosis,attenuation of morphine withdrawal, cardiovascular changes, oedema, suchas oedema caused by thermal injury, chronic inflammatory diseases suchas rheumatoid arthritis, asthma/bronchial hyperreactivity and otherrespiratory diseases including allergic rhinitis, inflammatory diseasesof the gut including ulcerative colitis and Crohn's disease, ocularinjury and ocular inflammatory diseases, proliferativevitreoretinopathy, irritable bowel syndrome and disorders of bladderfunction including cystitis and bladder detruser hyper-reflexia isreviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists",C. A. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J. Auton.Pharmacol. (1993) 13, 23-93.

For instance, substance P is believed inter alia to be involved in theneurotransmission of pain sensations Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act asa Pain Transmitter?" TIPS (1987) 8, 506-510!, specifically in thetransmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem,(1982) 25, 1009) and in arthritis Levine et al Science (1984) 226,547-549!. Tachykinins have also been implicated in gastrointestinal (GI)disorders and diseases of the GI tract such as inflammatory boweldisease Mantyh et al Neuroscience (1988) 25(3), 817-37 and D. Regoli in"Trends in Cluster Headache" Ed. Sicuteri et al Elsevier ScientificPublishers, Amsterdam (1987) page 85)! and emesis F. D. Tattersall etal, Eur. J. Pharmacol., (1993) 250, R5-R6!. It is also hypothesised thatthere is a neurogenic mechanism for arthritis in which substance P mayplay a role Kidd et al "A Neurogenic Mechanism for SymmetricalArthritis" in The Lancet, 11 Nov. 1989 and Gronblad et al,"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12), 1807-10!. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and osteoarthritis, and fibrositisO'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8!. Otherdisease areas where tachykinin antagonists are believed to be useful areallergic conditions Hamelet et al, Can. J. Phamacol. Physiol. (1988) 66,1361-7!, immunoregulation Lotz et al, Science (1988) 241, 1218-21 andKimball et al, J. Immunol. (1988) 141(10), 3564-9! vasodilation,bronchospasm, reflex or neuronal control of the viscera Mantyh et al,PNAS (1988) 85, 3235-9! and, possibly by arresting or slowingB-amyloid-mediated neurodegenerative changes Yankner et al, Science(1990) 250, 279-82! in senile dementia of the Alzheimer type,Alzheimer's disease and Down's Syndrome.

Tachykinin antagonists may also be useful in the treatment of small cellcarcinomas, in particular small cell lung cancer (SCLC) Langdon et al,Cancer Research (1992) 52, 4554-7!.

Substance P may also play a role in demyelinating diseases such asmultiple sclerosis and amyotrophic lateral sclerosis J. Luber-Narod etal, poster C.I.N.P. XVIIIth Congress, 28th Jun.-2nd Jul. 1992!, and indisorders of bladder function such as bladder detrusor hyper-reflexia(Lancet, 16th May 1992, 1239).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosus (Europeanpatent specification no. 0 436 334), ophthalmic disease such asconjuctivitis, vernal conjunctivitis, and the like, and cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis (European patent specification no. 0 394989).

European patent specification no. 0 577 394 (published 5th Jan. 1994)discloses morpholine and thiomorpholine tachykinin receptor antagonistsof the general formula ##STR1## wherein R^(1a) is a large variety ofsubstituents; R^(2a) and R^(3a) are inter alia hydrogen;

R^(4a) is inter alia ##STR2## R^(5a) is inter alia optionallysubstituted phenyl; R^(6a), R^(7a) and R^(8a) are a variety ofsubstituents;

X^(a) is O, S, SO or SO₂ ;

Y^(a) is inter alia O; and

Z^(a) is hydrogen or C₁₋₄ alkyl.

We have now found a further class of non-peptides which are potentantagonists of tachykinins, especially of substance P.

The present invention provides compounds of the formula (I): ##STR3##wherein R¹ represents hydrogen, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, C₁₋₆ alkoxy, C₁₋₄alkyl substituted by a hydroxy or C₁₋₄ alkoxy group, OCF₃, hydroxy,trifluoromethyl, trimethylsilyl, nitro, CN, SR^(a), SOR^(a) a, SO₂R^(a), COR^(a), CO₂ R^(a) or CONR^(a) R^(b) where R^(a) and R^(b) areeach independently hydrogen or C₁₋₄ alkyl;

R² and R³ each independently represent hydrogen, halogen, C₁₋₆ alkyl,C₁₋₆ alkoxy substituted by a C₁₋₄ alkoxy group, or trifluoromethyl;

R⁴ represents hydrogen, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, C₁₋₆ alkoxy, C₁₋₄ alkylsubstituted by a hydroxy or C₁₋₄ alkoxy group, OCF₃, hydroxy,trifluoromethyl, trimethylsilyl, nitro, CN, SR^(a), SOR^(a), SO₂ R^(a),COR^(a), CO₂ R^(a), CONR^(a) R^(b) where R^(a) and R^(b) are aspreviously defined;

R⁵ represents hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted bya C₁₋₄ alkoxy group, or trifluoromethyl;

R⁶ represents C₁₋₆ alkyl, optionally substituted by oxo, substituted bya 5-membered heteroaromatic ring selected from oxazole, thiazole,isoxazole, isothiazole, oxadiazole and thiadiazole, wherein eachheteroaromatic ring is substituted at the available carbon atom by agroup of the formula ZNR⁷ R⁸ where

Z is C₁₋₆ alkylene or C₃₋₆ cycloalkyl;

R⁷ is hydrogen or C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy or hydroxyl;

R⁸ is hydrogen or C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy, hydroxyl or a 4, 5 or 6membered heteroaliphatic ring containing one or two heteroatoms selectedfrom N, O and S;

or R⁷, R⁸ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by oneor two groups selected from hydroxy or C₁₋₄ alkoxy optionallysubstituted by a C₁₋₄ alkoxy or hydroxyl group, and optionallycontaining a double bond, which ring may optionally contain an oxygen orsulphur ring atom, a group S(O) or S(O)₂ or a second nitrogen atom whichwill be part of a NH or NR^(c) moiety where R^(c) is C₁₋₄ alkyloptionally substituted by hydroxy or C₁₋₄ alkoxy;

or R⁷, R⁸ and the nitrogen atom to which they are attached form anon-aromatic azabicyclic ring system of 6 to 12 ring atoms;

or Z, R⁷ and the nitrogen atom to which they are attached form aheteroaliphatic ring to 4 to 7 ring atoms which may optionally containan oxygen ring atom;

R⁹ and R¹⁰ each independently represent hydrogen or C₁₋₄ alkyl, or R⁹and R¹⁰ are joined so, together with the carbon atoms to which they areattached, there is formed a C₅₋₇ ring;

Y represents hydrogen or a C₁₋₄ alkyl group optionally substituted by ahydroxy group;

and pharmaceutically acceptable salts thereof.

Certain particularly apt compounds of the present invention includethose wherein R¹ is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or CF₃.

Most aptly R² is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or CF₃.

Most aptly R³ is hydrogen, fluorine, chlorine or CF₃.

Favourably R¹ is fluorine, chlorine or CF₃.

Favourably R² is hydrogen, fluorine, chlorine or CF₃.

Favourably R³ is hydrogen, fluorine, chlorine or CF₃.

Preferably R¹ and R² are in the 3 and 5 positions of the phenyl ring.

More preferably, R¹ is 3-fluoro or 3-CF₃.

More preferably, R² is 5-fluoro or 5-CF₃.

More preferably, R³ is hydrogen.

Most preferably, R¹ is 3-F or 3-CF₃, R² is 5-F or 5-CF₃ and R³ ishydrogen.

Most aptly R⁴ is hydrogen.

Most aptly R⁵ is hydrogen, fluorine, chlorine or CF₃.

Preferably R⁴ is hydrogen and R⁵ is hydrogen or 4-fluoro.

Most aptly R⁹ and R¹⁰ are each independently hydrogen or methyl.

Preferably R⁹ is hydrogen. Preferably R¹⁰ is hydrogen. Most preferablyR⁹ and R¹⁰ are both hydrogen.

Favourably R⁶ is C₁₋₆ alkyl, in particular CH₂, CH(CH₃) and CH₂ CH₂ andespecially CH₂, substituted by a 5-membered ring selected from: ##STR4##

Particularly preferred heterocyclic rings are selected from: ##STR5##

With respect to compounds of the formula (I), Z may be a linear,branched or cyclic group. Favourably Z contains 1 to 4 carbon atoms andmost favourably 1 or 2 carbon atoms. A particularly favourable group Zis CH₂.

With respect to compounds of the formula (I), R⁷ may aptly be a C₁₋₄alkyl group or a C₂₋₄ alkyl group substituted by a hydroxyl or C₁₋₂alkoxy group, R⁸ may aptly be a C₁₋₄ alkyl group or a C₁₋₄ alkyl groupsubstituted by a hydroxyl or C₁₋₂ alkoxy group, or R⁷ and R⁸ may belinked so that, together with the nitrogen atom to which they areattached, they form an azetidinyl, pyrrolidinyl, piperidyl, morpholino,thiomorpholino, piperazino or piperazino group substituted on thenitrogen atom by a C₁₋₄ alkyl group or a C₂₋₄ alkyl group substituted bya hydroxy or C₁₋₂ alkoxy group.

Where the group NR⁷ R⁸ represents a heteroaliphatic ring of 4 to 7 ringatoms and said ring contains a double bond, a particularly preferredgroup is 3-pyrroline.

Where the group NR⁷ R⁸ represents a non-aromatic azabicyclic ringsystem, such a system may contain between 6 and 12, and preferablybetween 7 and 10, ring atoms. Suitable rings include 5-azabicyclo2.1.1!hexyl, 5-azabicyclo 2.2.1!heptyl, 6-azabicyclo 3.2.1!octyl,2-azabicyclo 2.2.2!octyl, 6-azabicyclo 3.2.2!nonyl, 6-azabicyclo3.3.1!nonyl, 6-azabicyclo 3.2.2!decyl, 7-azabicyclo 4.3.1!decyl,7-azabicyclo 4.4.1!undecyl and 8-azabicyclo 5.4.1!dodecyl, especially5-azabicyclo 2.2.1!heptyl and 6-azabicyclo 3.2.1!octyl.

Where R⁸ represents a C₂₋₄ alkyl group substituted by a 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S, suitable rings include pyrrolidino, piperidino, piperazino,morpholino, or thiomorpholino. Particularly preferred are nitrogencontaining heteroaliphatic rings, especially pyrrolidino and morpholinorings.

Particularly suitable moieties ZNR⁷ R⁸ include those wherein Z is CH₂ orCH₂ CH₂ and NR⁷ R⁸ is amino, methylamino, dimethylamino, diethylamino,azetidinyl, pyrrolidino and morpholino.

Further preferred moieties represented by ZNR⁷ R⁸ are those wherein Z isCH₂ or CH₂ CH₂, R⁷ represents hydrogen, C₁₋₄ alkyl or C₃₋₆ cycloalkyland R⁸ is C₂₋₄ alkyl substituted by one or two substituents selectedfrom hydroxy, C₁₋₂ alkoxy, azetidinyl, pyrrolidino, piperidino,morpholino or thiomorpholino.

In particular, Z is preferably CH₂ and NR⁷ R⁸ is preferablydimethylamino, azetidinyl or pyrrolidino, especially dimethylamino.

As used herein, the term "alkyl" or "alkoxy" as a group or part of agroup means that the group is straight or branched. Examples of suitablealkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyland t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

The cycloalkyl groups referred to herein may represent, for example,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitablecycloalkylalkyl group may be, for example, cyclopropylmethyl.

As used herein, the terms "alkenyl" and "alkynyl" as a group or part ofa group means that the group is straight or branched. Examples ofsuitable alkenyl groups include vinyl and allyl. A suitable alkynylgroup is propargyl.

When used herein the term halogen means fluorine, chlorine, bromine andiodine. The most apt halogens are fluorine and chlorine of whichfluorine is preferred.

One favoured group of compounds of the present invention are of theformula (Ia): ##STR6## wherein R⁶ and Y are as defined in relation toformula (I) and

A¹ is fluorine or CF₃ ;

A² is fluorine or CF₃ ; and

A³ is hydrogen or fluorine;

and pharmaceutically acceptable salts thereof.

With respect to compounds of the formulae (I) and (Ia), Y may be aptly aC₁₋₄ alkyl optionally substituted by a hydroxy group. In particular Ymay be a methyl or hydroxymethyl group.

Specific compounds within the scope of this invention include:

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylaminomethyl)-1,2,5-oxadiazol-3-yl)methyl-3-(S)-phenylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylaminomethyl)-1,2,5-oxadiazol-3-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-piperidinomethyl)-1,2,4-oxadiazol-5-yl)methylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-dimethylaminomethyl)-1,2,4-oxadiazol-5-yl)methyl-3-(S)-phenylmorpholine;

and pharmaceutically acceptable salts thereof.

In a further aspect of the present invention, the compounds of formula(I) will preferably be prepared in the form of a pharmaceuticallyacceptable salt, especially an acid addition salt.

For use in medicine, the salts of the compounds of formula (a) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable acid such as hydrochloric acid, fumaricacid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the "parent drug" or "parent molecule")that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention have at least three asymmetriccentres, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The preferred compounds of the formula (I) will have the preferredstereochemistry of the 2- and 3-position that is possessed by thecompound of Example 1 (i.e. 2-(R), 3-(S)). Thus for example as shown informula (Ib) ##STR7##

The present invention further provides pharmaceutical compositionscomprising one or more compounds of formula (I) in association with apharmaceutically acceptable carrier or excipient.

Preferably the compositions according to the invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Preferred compositions for administration by injection include thosecomprising a compound of formula (I), as the active ingredient, inassociation with a surface-active agent (or wetting agent or surfactant)or in the form of an emulsion (as a water-in-oil or oil-in-wateremulsion).

Suitable surface-active agents include, in particular, non-ionic agents,such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) andother sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with asurface-active agent will conveniently comprise between 0.05 and 5%surface-active agent, and preferably between 0.1 and 2.5%. It will beappreciated that other ingredients may be added, for example mannitol orother pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fatemulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ andLipiphysan™. The active ingredient may be either dissolved in apre-mixed emulsion composition or alternatively it may be dissolved inan oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil,corn oil or almond oil) and an emulsion formed upon mixing with aphospholipid (e.g. egg phospholipids, soybean phospholipids or soybeanlecithin) and water. It will be appreciated that other ingredients maybe added, for example gylcerol or glucose, to adjust the tonicity of theemulsion. Suitable emulsions will typically contain up to 20% oil, forexample, between 5 and 20%. The fat emulsion will preferably comprisefat droplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, andhave a pH in the range of 5.5 to 8.0.

Particularly preferred emulsion compositions are those prepared bymixing a compound of formula (I) with Intralipid™ or the componentsthereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The present invention futher provides a process for the preparation of apharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity.

Thus, for example, an excess of tachykinin, and in particular substanceP, activity is implicated in a variety of disorders of the centralnervous system. Such disorders include mood disorders, such asdepression or more particularly depressive disorders, for example,single episodic or recurrent major depressive disorders and dysthymicdisorders, or bipolar disorders, for example, bipolar I disorder,bipolar II disorder and cyclothymic disorder; anxiety disorders, such aspanic disorder with or without agoraphobia, agoraphobia without historyof panic disorder, specific phobias, for example, specific animalphobias, social phobias, obsessive-compulsive disorder, stress disordersincluding post-traumatic stress disorder and acute stress disorder, andgeneralised anxiety disorders; schizophrenia and other psychoticdisorders, for example, schizophreniform disorders, schizoaffectivedisorders, delusional disorders, brief psychotic disorders, sharedpsychotic disorders and psychotic disorders with delusions orhallucinations; delerium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Alzheimer's disease, seniledementia, dementia of the Alzheimer's type, vascular dementia, and otherdementias, for example, due to HIV disease, head trauma, Parkinson'sdisease, Huntington's disease, Pick's disease, Creutzfeldt-Jakobdisease, or due to multiple aetiologies; Parkinson's disease and otherextra-pyramidal movement disorders such as medication-induced movementdisorders, for example, neuroleptic-induced parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremour; substance-relateddisorders arising from the use of alcohol, amphetamines (oramphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens,inhalants and aerosol propellants, nicotine, opioids, phenylglycidinederivatives, sedatives, hypnotics, and anxiolytics, whichsubstance-related disorders include dependence and abuse, intoxication,withdrawal, intoxication delerium, withdrawal delerium, persistingdementia, psychotic disorders, mood disorders, anxiety disorders, sexualdysfunction and sleep disorders; epilepsy; Down's syndrome;demyelinating diseases such as MS and ALS and other neuropathologicaldisorders such as peripheral neuropathy, for example diabetic andchemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia and other neuralgias; andcerebral vascular disorders due to acute or chronic cerebrovasculardamage such as cerebral infarction, subarachnoid haemorrhage or cerebraloedema.

Tachykinin, and in particular substance P, activity is also involved innociception and pain. The compounds of the present invention willtherefore be of use in the prevention or treatment of diseases andconditions in which pain predominates, including soft tissue andperipheral damage, such as acute trauma, osteoarthritis, rheumatoidarthritis, musculo-skeletal pain, particularly after trauma, spinalpain, myofascial pain syndromes, headache, episiotomy pain, and burns;deep and visceral pain, such as heart pain, muscle pain, eye pain,orofacial pain, for example, odontalgia, abdominal pain, gynaecologicalpain, for example, dysmenorrhoea, and labour pain; pain associated withnerve and root damage, such as pain associated with peripheral nervedisorders, for example, nerve entrapment and brachial plexus avulsions,amputation, peripheral neuropathies, tic douloureux, atypical facialpain, nerve root damage, and arachnoiditis; pain associated withcarcinoma, often referred to as cancer pain; central nervous systempain, such as pain due to spinal cord or brain stem damage; low backpain; sciatica; ankylosing spondylitis, gout; and scar pain.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of respiratory diseases, particularly thoseassociated with excess mucus secretion, such as chronic obstructiveairways disease, bronchopneumonia, chronic bronchitis, cystic fibrosisand asthma, adult respiratory distress syndrome, and bronchospasm;inflammatory diseases such as inflammatory bowel disease, psoriasis,fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;allergies such as eczema and rhinitis; hypersensitivity disorders suchas poison ivy; ophthalmic diseases such as conjunctivitis, vernalconjunctivitis, and the like; ophthalmic conditions associated with cellproliferation such as proliferative vitreoretinopathy; cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of neoplasms, including breast tumours,neuroganglioblastomas and small cell carcinomas such as small cell lungcancer.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of gastrointestinal (GI) disorders, includinginflammatory disorders and diseases of the GI tract such as gastritis,gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disordersassociated with the neuronal control of viscera, ulcerative colitis,Crohn's disease, irritable bowel syndrome and emesis, including acute,delayed or anticipatory emesis such as emesis induced by chemotherapy,radiation, toxins, viral or bacterial infections, pregnancy, vestibulardisorders, for example, motion sickness, vertigo, dizziness andMeniere's disease, surgery, migraine, variations in intercranialpressure, gastro-oesophageal reflux disease, acid indigestion, overindulgence in food or drink, acid stomach, waterbrash or regurgitation,heartburn, for example, episodic, nocturnal or meal-induced heartburn,and dyspepsia.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of a variety of other conditions including stressrelated somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; adverse immunological reactions such asrejection of transplanted tissues and disorders related to immuneenhancement or suppression such as systemic lupus erythematosus; plasmaextravasation resulting from cytokine chemotherapy, disorders of bladderfunction such as cystitis, bladder detrusor hyper-reflexia andincontinence; fibrosing and collagen diseases such as scleroderma andeosinophilic fascioliasis; disorders of blood flow caused byvasodilation and vasospastic diseases such as angina, vascular headache,migraine and Reynaud's disease; and pain or nociception attributable toor associated with any of the foregoing conditions, especially thetransmission of pain in migraine.

The compounds of formula (I) are also of value in the treatment of acombination of the above conditions, in particular in the treatment ofcombined post-operative pain and post-operative nausea and vomiting.

The compounds of formula (I) are particularly useful in the treatment ofemesis, including acute, delayed or anticipatory emesis, such as emesisinduced by chemotherapy, radiation, toxins, pregnancy, vestibulardisorders, motion, surgery, migraine, and variations in intercranialpressure. Most especially, the compounds of formula (I) are of use inthe treatment of emesis induced by antineoplastic (cytotoxic) agentsincluding those routinely used in cancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents, forexample, nitrogen mustards, ethyleneimine compounds, alkyl sulphonatesand other compounds with an alkylating action such as nitrosoureas,cisplatin and dacarbazine; antimetabolites, for example, folic acid,purine or pyrimidine antagonists; mitotic inhibitors, for example, vincaalkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.

Particular examples of chemotherapeutic agents are described, forinstance, by D. J. Stewart in Nausea and Vomiting: Recent Research andClinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton,Fla., U.S.A. (1991) pages 177-203, especially page 188. Commonly usedchemotherapeutic agents include cisplatin, dacarbazine (DTIC),dactinomycin, mechlorethamine (nitrogen mustard), streptozocin,cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin(adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine,etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine,bleomycin and chlorambucil R. J. Gralla et al in Cancer TreatmentReports (1984) 68(1), 163-172!.

The compounds of formula (I) are also of use in the treatment of emesisinduced by radiation including radiation therapy such as in thetreatment of cancer, or radiation sickness; and in the treatment ofpost-operative nausea and vomiting.

It will be appreciated that the compounds of formula (I) may bepresented together with another therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use for the reliefof emesis. Such combined preparations may be, for example, in the formof a twin pack.

A further aspect of the present invention comprises the compounds offormula () in combination with a 5-HT₃ antagonist, such as ondansetron,granisetron or tropisetron, or other anti-emetic medicaments, forexample, a dopamine antagonist such as metoclopramide. Additionally, acompound of formula (I) may be administered in combination with ananti-inflammatory corticosteroid, such as dexamethasone. Furthermore, acompound of formula (I) may be administered in combination with achemotherapeutic agent such as an alkylating agent, antimetabolite,mitotic inhibitor or cytotoxic antibiotic, as described above. Ingeneral, the currently available dosage forms of the known therapeuticagents for use in such combinations will be suitable.

When tested in the ferret model of cisplatin-induced emesis described byF. D. Tattersall et al, in Eur. J. pharmacol., (1993) 250, R5-R6, thecompounds of the present invention were found to attenuate the retchingand vomiting induced by cisplatin.

The compounds of formula (I) are also particularly useful in thetreatment of pain or nociception and/or inflammation and disordersassociated therewith such as, for example, neuropathy, such as diabeticand chemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis and headache, includingmigraine, acute or chronic tension headache, cluster headache,temporomandibular pain, and maxillary sinus pain.

The present invention further provides a compound of formula (I) for usein therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment of physiological disorders associated withan excess of tachykinins, especially substance P.

The present invention also provides a method for the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

For the treatment of certain conditions it may be desirable to employ acompound according to the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of formula (I) may beused in conjunction with a bronchodilator, such as a β₂ -adrenergicreceptor antagonist or tachykinin antagonist which acts at NK-2receptors. The compound of formula (I) and the bronchodilator may beadministered to a patient simultaneously, sequentially or incombination.

Likewise, a compound of the present invention may be employed with aleukotriene antagonists, such as a leukotriene D₄ antagonist such as acompound selected from those disclosed in European patent specificationnos. 0 480 717 and 0 604 114 and in U.S. Pat. Nos. 4,859,692 and5,270,324. This combination is particularly useful in the treatment ofrespiratory diseases such as asthma, chronic bronchitis and cough.

The present invention accordingly provides a method for the treatment ofa respiratory disease, such as asthma, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of formula (I) and an effective amount of a bronchodilator.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

It will be appreciated that for the treatment or prevention of migraine,a compound of the present invention may be used in conjunction withother anti-migraine agents, such as ergotamines or 5-HT₁ agonists,especially sumatriptan.

Likewise, for the treatment of behavioural hyperalgesia, a compound ofthe present invention may be used in conjunction with an antagonist ofN-methyl D-aspartate (NMDA), such as dizocilpine.

For the treatment or prevention of inflammatory conditions in the lowerurinary tract, especially cystitis, a compound of the present inventionmay be used in conjunction with an anti-inflammatory agent such as abradykinin receptor antagonist.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

It will be appreciated that for the treatment or prevention of pain ornociception, a compound of the present invention may be used inconjunction with other analgesics, such as acetaminophen (paracetamol),aspirin and other NSAIDs and, in particular, opioid analgesics,especially morphine. Specific anti-inflammatory agents includediclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam andsulindac. Suitable opioid analgesics of use in conjunction with acompound of the present invention include morphine, codeine,dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone,levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol,fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxypheneand pentazocine; or a pharmaceutically acceptable salt thereof.Preferred salts of these opioid analgesics include morphine sulphate,morphine hydrochloride, morphine tartrate, codeine phosphate, codeinesulphate, dihydrocodeine bitartrate, diacetylmorphine hydrochloride,hydrocodone bitartrate, hydromorphone hydrochloride, levorphanoltartrate, oxymorphone hydrochloride, alfentanil hydrochloride,buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate,meperidine hydrochloride, methadone hydrochloride, nalbuphinehydrochloride, propoxyphene hydrochloride, propoxyphene napsylate(2-naphthalenesulphonic acid (1:1) monohydrate), and pentazocinehydrochloride.

Therefore, in a further aspect of the present invention, there isprovided a pharmaceutical composition comprising a compound of thepresent invention and an analgesic, together with at least onepharmaceutically acceptable carrier or excipient.

In a further or alternative aspect of the present invention, there isprovided a product comprising a compound of the present invention and ananalgesic as a combined preparation for simultaneous, separate orsequential use in the treatment or prevention of pain or nociception.

The excellent pharmacological profile of the compounds of the presentinvention offers the opportunity for their use in therapy at low dosesthereby minimising the risk of unwanted side effects.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day.

For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

In the treatment of emesis using an injectable formulation, a suitabledosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005to 5 mg/kg per day, and especially 0.0 1 to 1 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

It will be appreciated that the amount of a compound of formula (I)required for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

According to a general process (A), the compounds according to theinvention may be prepared from compounds of formula (II) ##STR8##wherein R¹, R², R³, R⁴, R⁵, R⁹, R¹⁰ and Y are as defined in relation toformula (I) by reaction with a compound of formula (III):

    LG--R.sup.6a                                               (III)

where R^(6a) is a group of the formula R⁶ as defined in relation toformula (I) or a precursor therefor and LG is a leaving group such as analkyl-- or arylsulphonyloxy group (e.g. mesylate or tosylate) or ahalogen atom (e.g. bromine, chlorine or iodine); and, if R^(6a) is aprecursor group, converting it to a group R⁶ (in which process anyreactive group may be protected and thereafter deprotected if desired).

This reaction may be performed in conventional manner, for example in anorganic solvent such as dimethylformamide in the presence of an acidacceptor such as potassium carbonate.

Thus, for instance, where R⁶ is a C₁₋₆ alkyl group substituted by a1,2,5-oxadiazolyl or 1,2,5-thiadiazolyl group, each of whichheteroaromatic rings is substituted by ZNR⁷ R⁸, may be prepared by thereaction of a compound of formula (II) with a compound of formula (IV)##STR9## where m is an integer from 1 to 6, n is an integer from 1 to 6,X is O or S and each LG independently represents a leaving group aspreviously defined, followed by reaction of the resultant compound withan amine of formula NHR⁷ R⁸ to complete the group ZNR⁷ R⁸.

According to another process (B), compounds of formula (I) wherein R⁶represents a C₁₋₆ alkyl group substituted by a 1,2,4-oxadiazolyl or1,2,4-thiadiazolyl group, each of which heteroaromatic rings issubstituted by ZNR⁷ R⁸, may be prepared by reaction of a compound offormula (V): ##STR10## wherein m is an integer from 1 to 6, with acompound of formula (VI): ##STR11## in the presence of a base.

Suitable bases of use in the reaction include alkali metals, such as,for example, sodium, and alkali metal hydrides, such as, for example,sodium hydride.

The reaction is conveniently effected in a suitable organic solvent.Which solvents will be appropriate will depend on the nature of the baseused. For example, where the base used is an alkali metal, suitablesolvents will include alcohols, for example, ethanol, whereas where thebase used is an alkali hydride, suitable solvents will include ethers,for example, tetrahydrofuran.

Preferably the reaction is conducted at elevated temperature, such asthe reflux temperature of the chosen solvent.

Compounds of formula (I) wherein R⁶ is C₁₋₆ alkyl substituted bythiazolyl may be prepared from compounds of formula (I) wherein R⁶ isC₁₋₆ alkyl substituted by CSNH₂ by reaction with a compound of formulaHal--CH₂ C(O)--R⁶, where Hal is a halogen atom, such as bromine,chlorine or iodine, and R⁶⁰ represents H or a suitable substituent.

Intermediates of the formula (I) may be prepared as shown in thefollowing Scheme in which Ar¹ represents the R¹, R², R³ substitutedphenyl group; Ar² represents the R⁴, R⁵ substituted phenyl group and Phrepresents phenyl: ##STR12##

L-Selectride is lithium tri-sec-butylborohydride.

The following references describe methods which may be applied by theskilled worker to the chemical synthesis set forth above once theskilled worker has read the disclosure herein:

(i) D. A. Evans et al., J. Am. Chem. Soc., (1990) 112, 4011.

(ii) I. Yanagisawa et al., J. Med. Chem., (1984) 27, 849.

(iii) R. Duschinsky et al., J. Am. Chem. Soc., (1948) 70, 657.

(iv) F. N. Tebbe et al., J. Am. Chem. Soc., (1978) 100, 3611.

(v) N. A. Petasis et al., J. Am. Chem. Soc., (1990) 112, 6532.

(vi) K. Takai et al., J. Org. Chem., (1987) 52, 4412.

Intermediates of formula (V) may be prepared by the reaction of acompound of formula (II) with a halogenated ester such as methylbromoacetate. The reaction is conveniently effected in the presence of abase such as an alkali metal carbonate, for example, potassium carbonatein a suitable anhydrous organic solvent such as, for example, anhydrousdimethylformamide, preferably at a temperature between 50° C. and 150°C.

Intermediates of formula (VI) are either commercially available or maybe prepared by conventional methodology. For example, by the reaction ofa suitable acetonitrile derivative with hydroxyamine hydrochloride in anorganic solvent such as ethanol, conveniently at room temperature.

Where they are not commercially available, the intermediates of formula(III) above may be prepared by the procedures described in theaccompanying Examples or by alternative procedures which will be readilyapparent to one skilled in the art.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The exemplified compounds of this invention were tested by the methodsset out at pages 36 to 39 of International Patent Specification No. WO93/01165. The compounds or, in the case of prodrugs, the parentcompounds, were found to be active with IC₅₀ at the NK₁ receptor of lessthan 1 μM on said test method.

The following non-limiting Examples serve to illustrate the preparationof compounds of the present invention:

DESCRIPTION 1

(S)-(4-Fluorophenyl)glycine

Via Chiral Synthesis:

Step A: 3-(4-Fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone

An oven-dried, 1 L 3-necked flask, equipped with a septum, nitrogeninlet, thermometer, and a magnetic stirring bar, was flushed withnitrogen and charged with a solution of 5.09 g (33.0 mmol) of4-fluorophenylacetic acid in 100 ml of anhydrous ether. The solution wascooled to -10° C. and treated with 5.60 ml (40.0 mmol) of triethylaminefollowed by 4.30 ml (35.0 mmol) of trimethylacetyl chloride. A whiteprecipitate formed immediately. The resulting mixture was stirred at-10° C. for 40 minutes, then cooled to -78° C.

An oven-dried, 250 ml round bottom flask, equipped with a septum and amagnetic stirring bar, was flushed with nitrogen and charged with asolution of 5.31 g (30.0 mmol) of 4-(S)-benzyl-2-oxazolidinone in 40 mlof dry THF. The solution was stirred in a dry ice/acetone bath for 10minutes, then 18.8 ml of 1.6M n-butyllithium solution in hexanes wasslowly added. After 10 minutes, the lithiated oxazolidinone solution wasadded, via cannula, to the above mixture in the 3-necked flask. Thecooling bath was removed from the resulting mixture and the temperaturewas allowed to rise to 0° C. The reaction was quenched with 100 ml ofsaturated aqueous ammonium chloride solution, transferred to a 11 flask,and the ether and THF were removed in vacuo. The concentrated mixturewas partitioned between 300 ml of methylene chloride and 50 ml of waterand the layers were separated. The organic layer was washed with 100 mlof 2N aqueous hydrochloric acid solution, 300 ml of saturated aqueoussodium bicarbonate solution, dried over magnesium sulfate andconcentrated in vacuo. Flash chromatography on 400 g of silica gel using3:2 v/v hexanes/ether as the eluant afforded 8.95 g of an oil thatslowly solidified on standing. Recrystallisation from 10:1 hexanes/etherafforded 7.89 g (83%) of the title compound as a white solid: mp 64°-66°C. MS (FAB): m/z 314 (M⁺ +H, 100%), 177 (M-ArCH₂ CO+H, 85%). ¹ H NMR(400 MHz, CDCl₃) δ 2.76 (1H, dd, J=13.2, 9.2), 3.26 (dd, J=13 2, 3.2),4.16-4.34 (4H, m), 4.65 (1H, m), 7.02-7.33 (9H, m). Anal. Calcd for C₁₈H₁₆ FNO₃ ; C, 69.00; H, 5.15; N, 4.47; F, 6.06; Found: C, 68.86; H,5.14; N, 4.48; F, 6.08.

Step B:3-((S)-Azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazolidinone

An oven-dried, 1 l 3-necked flask, equipped with a septum, nitrogeninlet, thermometer, and a magnetic stirring bar, was flushed withnitrogen and charged with a solution of 58.0 ml of 1M potassiumbis(trimethylsilyl)amide solution in toluene and 85 ml of THF and wascooled to -78° C. An oven-dried 250 ml round-bottomed flask, equippedwith a septum and a magnetic stirring bar, was flushed with nitrogen andcharged with a solution of 7.20 g (23.0 mmol) of3-(4-fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone (from Step A) in40 ml of THF. The acyl oxazolidinone solution was stirred in a dryice/acetone bath for 10 minutes, then transferred, via cannula, to thepotassium bis(trimethylsilyl)amide solution at such a rate that theinternal temperature of the mixture was maintained below -70° C. Theacyl oxazolidinone flask was rinsed with 15 ml of THF and the rinse wasadded, via cannula, to the reaction mixture and the resulting mixturewas stirred at -78° C. for 30 minutes. An oven-dried, 250 mlround-bottomed flask, equipped with a septum and a magnetic stirringbar, was flushed with nitrogen and charged with a solution of 10.89 g(35.0 mmol) of 2,4,6-triisopropylphenylsulfonyl azide in 40 ml of THF.The azide solution was stirred in a dry ice/acetone bath for 10 minutes,then transferred, via cannula, to the reaction mixture at such a ratethat the internal temperature of the mixture was maintained below -70°C. After 2 minutes, the reaction was quenched with 6.0 ml of glacialacetic acid, the cooling bath was removed and the mixture was stirred atroom temperature for 18 hours. The quenched reaction mixture waspartitioned between 300 ml of ethyl acetate and 300 ml of 50% saturatedaqueous sodium bicarbonate solution. The organic layer was separated,dried over magnesium sulfate, and concentrated in vacuo. Flashchromatography on 500 g of silica gel using 2:1 v/v, then 1:1 v/vhexanes/methylene chloride as the eluant afforded 5.45 g (67%) of thetitle compound as an oil. IR Spectrum (neat, cm⁻¹): 2104, 1781, 1702. ¹H NMR (400MHz, CDCl₃) δ 2.86 (1H, dd, J=13.2, 9.6), 3.40 (1H, dd,J=13.2, 3.2), 4.09-4.19 (2H, m), 4.62-4.68 (1H, m), 6.14 (1H, s),7.07-7.47 (9H, m). Anal. Calcd. for C₁₈ H₁₅ FN₄ O₃ ; C 61.01; H, 4.27;N, 15.81; F, 5.36; Found: C, 60.99; H, 4.19; N, 15.80; F, 5.34.

Step C: (S)-Azido-(4-fluorophenyl)acetic acid

A solution of 5.40 g (15.2 mmol) of3-((S)-azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazolidinone (fromStep B) in 200 ml of 3:1 v/v THF/water was stirred in an ice bath for 10minutes. 1.28 g (30.4 mmol) of lithium hydroxide monohydrate was addedin one portion and the resulting mixture was stirred cold for 30minutes. The reaction mixture was partitioned between 100 ml ofmethylene chloride and 100 ml of 25% saturated aqueous sodiumbicarbonate solution and the layers were separated. The aqueous layerwas washed with 2×100 ml of methylene chloride and acidified to pH 2with 2N aqueous hydrochloric acid solution. The resulting mixture wasextracted with 2×100 ml of ethyl acetate; the extracts were combined,washed with 50 ml of saturated aqueous sodium chloride solution, driedover magnesium sulfate, and concentrated in vacuo to afford 2.30 g (77%)of the title compound as an oil that was used in the following stepwithout further purification. IR Spectrum (neat, cm⁻¹): 2111, 1724. ¹ HNMR (400 MHz, CDCl₃) δ 5.06 (1H, s), 7.08-7.45 (4H, m), 8.75 (1H, br s).

Step D: (S)-(4-Fluorophenyl)glycine

A mixture of 2.30 g (11.8 mmol) of (S)-azido-(4-fluorophenyl)acetic acid(from Step C), 2.50 mg 10% palladium on carbon catalyst and 160 ml 3:1v/v water/acetic acid was stirred under an atmosphere of hydrogen for 18hours. The reaction mixture was filtered through Celite and the flaskand filter cake were rinsed well with ˜1 l of 3:1 v/v water/acetic acid.The filtrate was concentrated in vacuo to about 50 ml of volume. 300 mlof toluene was added and the mixture concentrated to afford a solid. Thesolid was suspended in 1:1 v/v methanol/ether, filtered and dried toafford 1.99 g (100%) of the title compound. ¹ H NMR (400 MHz, D₂ O+NaOD)δ 3.97 (1H, s), 6.77 (2H, app t, J=8.8), 7.01 (2H, app t, J=5.6).

Via Resolution

Step A' (4-Fluorophenyl)acetyl chloride

A solution of 150 g (0.974 mol) of 4-(fluorophenyl)acetic acid and 1 mlof N,N-dimethylformamide in 500 ml of toluene at 40° C. was treated with20 ml of thionyl chloride and heated to 40° C. An additional 61.2 ml ofthionyl chloride was added dropwise over 1.5 hours. After the addition,the solution was heated at 50° C. for 1 hour, the solvent was removed invacuo and the residual oil was distilled at reduced pressure (1.5 mmHg)to afford 150.4 g (89.5%) of the title compound, bp=68°-70° C.

Step B': Methyl 2-bromo-3-(4-fluorophenyl)acetate

A mixture of 150.4 g (0.872 mol) of 4-(fluorophenyl)acetyl chloride(from Step A') and 174.5 g (1.09 mol) of bromine was irradiated at40°-50° C. with a quartz lamp for 5 hours. The reaction mixture wasadded dropwise to 400 ml of methanol and the solution was stirred for 16hours. The solvent was removed in vacuo and the residual oil wasdistilled at reduced pressure (1.5 mmHg) to afford 198.5 g (92%) of thetitle compound, bp=106°-110° C.

Step C': Methyl (±)-(4-fluorophenyl)glycine

A solution of 24.7 g (0.1 mol) of methyl2-bromo-2-(4-fluorophenyl)acetate (from Step B') and 2.28 g (0.01 mol)of benzyl triethylammonium chloride in 5 ml of methanol was treated with6.8 g (0.105 mol) of sodium azide and the resulting mixture was stirredfor 20 hours at room temperature. The reaction mixture was filtered; thefiltrate was diluted with 50 ml of methanol and hydrogenated in thepresence of 0.5 g of 10% Pd/C at 50 psi for 1 hour. The solution wasfiltered and the solvent removed in vacuo. The residue was partitionedbetween 10% aqueous sodium carbonate solution and ethyl acetate. Theorganic phase was washed with water, saturated aqueous sodium chloridesolution dried over magnesium sulfate and concentrated in vacuo toafford 9.8 g of the title compound as an oil.

Step D': Methyl (S)-(4-fluorophenyl)glycinate

A solution of 58.4 g of methyl (±) 4-(fluorophenyl)glycinate (from StepC') in 110 ml of 7:1 v/v ethanol/water was mixed with a solution of 28.6g (0.0799 mol) of O,O'-(+)-dibenzoyltartaric acid ((+)-DBT) (28.6 g,0.0799 mol) in 110 ml of 7:1 v/v ethanol:water and the resultingsolution was allowed to age at room temperature. Ethyl acetate (220 ml)was added after crystallisation was complete and the resulting mixturewas cooled to -20° C. and filtered to afford 32.4 g of methyl(S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee=93.2%). The motherliquors were concentrated in vacuo and the free base was liberated bypartitioning between ethyl acetate and aqueous sodium carbonatesolution. A solution of free base, so obtained, in 110 ml of 7:1 v/vethanol/water was mixed with a solution of 28.6 g (0.0799 mol) ofO,O'-(-)-dibenzoyltartaric acid ((-)-DBT) (28.6 g, 0.0799 mol) in 110 mlof 7:1 v/v ethanol:water and the resulting solution was allowed to ageat room temperature. Ethyl acetate (220 ml) was added aftercrysallisation was complete and the resulting mixture was cooled to -20°C. and filtered to afford 47.0 g of methyl(R)-(4-fluorophenyl)glycinate, (-)-DBT salt (ee=75.8%). Recycling of themother liquors and addition of (+)-DBT gave a second crop of 7.4 g of(S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee=96.4%). The two crops ofthe (S)-amino ester (39.8 g) were combined in 200 ml of 7:1 v/vethanol/water, heated for 30 minutes and cooled to room temperature.Addition of ethyl acetate, cooling, and filtration afforded 31.7 g of(S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee>98%). Enantiomericexcess was determined by chiral HPLC (Crownpak CR(+) 5% MeOH in aq HClO₄pH2 1.5 ml/min 40° C. 200 nm).

A mixture of 17.5 g of (S)-(4-fluorophenyl)glycinate, (+)-DBT salt and32 ml of 5.5N HCl (32 ml) was heated at reflux for 1.5 hours. Thereaction mixture was concentrated in vacuo and the residue was dissolvedin 40 ml of water. The aqueous solution was washed (3×30 ml of ethylacetate) and the layers were separated. The pH of the aqueous layer wasadjusted to 7 using ammonium hydroxide and the precipitated solid wasfiltered to afford 7.4 g of the title compound (ee=98.8%).

DESCRIPTION 2

4-Benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone

Step A: N-Benzyl-(S)-(4-fluorophenyl)glycine

A solution of 1.87 g (11.05 mmol) of (S)-(4-fluorophenyl)-glycine (fromDescription 1) and 1.12 ml (11.1 mmol) of benzaldehyde in 11.1 ml of 1Naqueous sodium hydroxide solution and 1 ml of methanol at 0° C. wastreated with 165 mg (4.4 mmol) of sodium borohydride. The cooling bathwas removed and the resulting mixture was stirred at room temperaturefor 30 minutes. Second portions of benzaldehyde (1.12 ml (11.1 mmol))and sodium borohydride (165 mg (4.4 mmol) were added to the reactionmixture and stirring was continued for 1.5 hours. The reaction mixturewas partitioned between 100 ml of ether and 50 ml of water and thelayers were separated. The aqueous layer was separated and filtered toremove a small amount of insoluble material. The filtrate was acidifiedto pH 5 with 2N aqueous hydrochloric acid solution and the solid thathad precipitated was filtered, rinsed well with water, then ether, anddried to afford 1.95 g of the title compound. ¹ H NMR (400 MHz, D₂O+NaOD) δ 3.33 (2H, AB q, J=8.4), 3.85 (1H, s), 6.79-7.16 (4H, m).

Step B: 4-Benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone

A mixture of 1.95 g (7.5 mmol) of N-benzyl (S)-(4-fluorophenyl)glycine,3.90 ml (22.5 mmol) of N,N-diisopropyl-ethylamine, 6.50 ml (75.0 mmol)of 1,2-dibromoethane and 40 ml of N,N-dimethylformamide was stirred at100° C. for 20 hours (dissolution of all solids occurred on warming).The reaction mixture was cooled and concentrated in vacuo. The residuewas partitioned between 250 ml of ether and 100 ml of 0.5N potassiumhydrogen sulfate solution and the layers were separated. The organiclayer was washed with 100 ml of saturated aqueous sodium bicarbonatesolution, 3×150 ml of water, dried over magnesium sulfate, andconcentrated in vacuo. Flash chromatography on 125 g of silica gel using3:1 v/v hexanes/ether as the eluant afforded 1.58 g (74%) of the titlecompound as an oil. ¹ H NMR (400 MHz, CDCl₃) δ 2.65 (1H, dt, J=3.2,12.8), 3.00 (1H, dt, J=12.8, 2.8), 3.16 (1H, d, J=13.6), 3.76 (1H, d,J=13.6), 4.24 (1H, s), 4.37 (1H, dt, J=13.2, 3.2), 4.54 (1H, dt, J=2.8,13.2), 7.07-7.56 (9H, m).

DESCRIPTION 3

4-Benzyl-2-(R)-(35-bis(trifluoromethyl)benzoyloxy)-3-(S)-(4-fluorophenyl)morpholine

A solution of 2.67 g (10.0 mmol) of4-benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone (Description 2) in 40 mlof dry THF was cooled to -78° C. The cold solution was treated with 12.5ml of 1.0M L-Selectride® solution in THF, maintaining the internalreaction temperature below -70° C. The resulting solution was stirredcold for 45 minutes and the reaction was charged with 3.60 ml (20.0mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellowmixture was stirred cold for 30 minutes and the reaction was quenchedwith 50 ml of saturated aqueous sodium bicarbonate solution. Thequenched mixture was partitioned between 300 ml of ether and 50 ml ofwater and the layers were separated. The organic layer was dried overmagnesium sulfate. The aqueous layer was extracted with 300 ml of ether;the extract was dried and combined with the original organic layer. Thecombined organics were concentrated in vacuo. Flash chromatography on150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded4.06 g (80%) of the title compound as a solid. ¹ H NMR (200 MHz, CDCl₃)δ 2.50 (1H, dt, J=3.4, 12.0), 2.97 (1H, app d, J=12.0), 2.99 (1H, d,J=13.6), 3.72-3.79 (1H, m), 3.82 (1H, d, J=2.6), 4.00 (1H, d, J=13.6),4.20 (dt, J=2.4, 11.6), 6.22 (1H, d, J=2.6), 7.22-7.37 (7H, m), 7.57(2H, app d, J=6.8), 8.07 (1H, s), 8.47 (2H, s). MS (FAB) m/z 528 (M+H,25%), 270 (100%). Anal. Calcd for C₂₆ H₂₀ F₇ NO₃ : C, 59.21; H, 3.82; N,2.66; F, 25.21. Found: C, 59.06; H, 4.05; N, 2.50; F, 25.18.

DESCRIPTION 4

4-Benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-(4-fluorophenyl)morpholine

Step A: Dimethyl titanocene

A solution of 2.49 g (10.0 mmol) of titanocene dichloride in 50 ml ofether in the dark at 0° C. was treated with 17.5 ml of 1.4Mmethyllithium solution in ether maintaining the internal temperaturebelow 5° C. The resulting yellow/orange mixture was stirred at roomtemperature for 30 minutes and the reaction was quenched by slowlyadding 25 g of ice. The quenched reaction mixture was diluted with 50 mlof ether and 25 ml of water and the layers were separated. The organiclayer was dried over magnesium sulfate and concentrated in vacuo toafford 2.03 g (98%) of the title compound as a light-sensitive solid.The dimethyl titanocene could be stored as a solution in toluene at 0°C. for at least 2 weeks without apparent chemical degradation. ¹ H NMR(200 MHz, CDCl₃) δ -0.15 (6H, s), 6.06 (10H, s).

Step B:4-Benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3(S)-(4-fluorophenyl)morpholine

A solution of the compound of Description 3 (2.50 g, 4.9 mmol) and 2.50g (12.0 mmol) of dimethyl titanocene (from Step A) in 35 ml of 11 v/vTHF/toluene was stirred in an oil bath at 80° C. for 16 hours. Thereaction mixture was cooled and concentrated in vacuo. Flashchromatography on 150 g of silica gel using 3:1 v/v hexanes/methylenechloride as the eluant afforded 1.71 g (69%) of the title compound as asolid. An analytical sample was obtained via recrystallisation fromisopropanol: ¹ H NMR (400 MHz, CDCl₃) δ 2.42 (1H, dt, J=3.6, 12.0), 2.90(1H, app d, J=12.0), 2.91 (1H, d, J=13.6), 3.62-3.66 (1H, m), 3.72 (1H,d, J=2.6), 3.94 (1H, d, J=13.6), 4.09 (1H, dt, J=2.4, 12.0), 4.75 (1H,d, J=3.2), 4.82 (1H, d, J=3.2), 5.32 (1H, d, J=2.6), 7.09 (2H, t,J=8.8), 7.24-7.33 (5H, m), 7.58-7.62 (2H, m), 7.80 (1H, s), 7.90 (2H,s); MS (FAB) 526 (M+H, 75%), 270 (100%). Anal. Calcd for C₂₇ H₂₂ F₇ NO₂: C, 61.72; H, 4.22; N, 2.67; F, 25.31. Found: C, 61.79; H, 4.10; N,2.65; F, 25.27%.

DESCRIPTION 5

2-(R)-(1-(R)-(35-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine

The compound of Description 4 (4.0 g) was dissolved in ethyl acetate (50ml) and isopropanol (16 ml). To this solution was added palladium oncharcoal (1.5 g) and the mixture was hydrogenated at 40 psi for 36 h.The catalyst was removed by filtration through Celite and the solventswere removed in vacuo. The residue was purified by flash chromatographyon silica using 100% ethyl acetate and then 1-10% methanol in ethylacetate. This afforded isomer A 500 mg (15%) and isomer B 2.6 g (80%) asclear oils--isomer B crystallised on standing. For the title compound: ¹H NMR (400 MHz, CDCl₃) δ 1.16 (3H, d, J=6.8MHz), 1.80 (1H, br s), 3.13(1H, dd, J=3.2, 12.4 Hz), 3.23 (1H, dt, J=3.6, 12.4 Hz), 3.63 (1H, dd,J=2.4, 11.2 Hz), 4.01 (1H, d, J=2.4 Hz), 4.13 (1H, dt, J=3.2, 12.0 Hz),4.42 (1H, d, J=2.4 Hz), 4.19 (1H, q, J=6.8 Hz), 7.04-7.09 (2H, m),7.27-7.40 (4H, m), 7.73 (1H, s); MS (FAB) 438 (M+H, 75%), 180 (100%).

HCl salt formation. To a solution of the free base (0.77 g) in diethylether (10 ml) was added 1M-HCl in methanol (1.75 ml). The solution wasevaporated to dryness and on addition of diethyl ether crystals formed.The solution was filtered and the residue washed with diethyl ether togive the title compound hydrochloride salt mp 248°-250° C. Found: C,50.46; H, 3.85; N, 3.01; Cl, 7.31. C₂₀ H₁₈ F₇ NO₂.HCl requires C, 50.70;H, 4.04; N, 2.96; Cl, 7.48%.

DESCRIPTION 6

4-Benzyl-3-(S)-phenyl-2-morpholinone

Step A: N-Benzyl-(S)-phenylglycine

A solution of 1.51 g (10.0 mmol) of (S)-phenylglycine in 5 ml of 2Naqueous sodium hydroxide solution was treated with 1.0 ml (10.0 mmol) ofbenzaldehyde and stirred at room temperature for 20 minutes. Thesolution was diluted with 5 ml of methanol, cooled to 0° C., andcarefully treated with 200 mg (5.3 mmol) of sodium borohydride. Thecooling bath was removed and the reaction mixture was stirred at roomtemperature for 1.5 hours. The reaction was diluted with 20 ml of waterand extracted with 2×25 ml of methylene chloride. The aqueous layer wasacidified with concentrated hydrochloric acid to pH 6 and the solid thatprecipitated was filtered, washed with 50 ml of water, 50 ml of 1:1 v/vmethanol/ethyl ether and 50 ml of ether, and dried to afford 1.83 g(76%) of product, mp 230°-232° C. Anal. Calcd for C₁₅ H₁₅ NO₂ : C,74.66; H, 6.27; N, 5.81. Found: C, 74.17; H, 6.19; N, 5.86.

Step B: 4-Benzyl-3-(S)-phenyl-2-morpholinone

A mixture of 4.00 g (16.6 mmol) of N-benzyl-(S)-phenylglycine (from StepA) 5.00 g (36.0 mmol) of potassium carbonate, 10.0 ml of1,2-dibromoethane and 25 ml of N,N-dimethylformamide was stirred at 100°C. for 20 hours. The mixture was cooled and partitioned between 200 mlof ethyl ether and 100 ml of water. The layers were separated and theorganic layer was washed with 3×50 ml of water, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography on 125 g of silica gel eluting with 9:1 v/v, then 4:1hexaneslethyl ether to afford 2.41 g (54%) of the product as a solid, mp98°-100° C. ¹ H NMR (250 MHz, CDCl₃) δ 2.54-2.68 (1H, m), 2.96 (1H, dt,J=12.8, 2.8), 3.14 (1H, d, J=13.3), 3.75 (1H, d, J=13.3), 4.23 (1H, s),4.29-4.37 (1H, m), 4.53 (dt, J=3.2, 11.0), 7.20-7.56 (10H, m). MS (FAB):m/z 268 (M+H; 100%). Anal. Calcd for C₁₇ H₁₇ NO₂ : C, 76.38; H, 6.41; N,5.24. Found: C, 76.06; H, 6.40; N, 5.78.

DESCRIPTION 7

4-Benzyl-2-(R)-(3,5-bis(trifluoromethyl)benzoyloxy)-3-(S)-phenylmorpholine

A solution of 2.67 g (10.0 mmol) of the compound of Description 6 in 40ml of dry THF was cooled to -78° C. The cold solution was treated with12.5 ml of 1.0M L-Selectride® solution in THF, maintaining the internalreaction temperature below -70° C. The resulting solution was stirredcold for 45 minutes and the reaction was charged with 3.60 ml (20.0mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellowmixture was stirred cold for 30 minutes and the reaction was quenchedwith 50 ml of saturated aqueous sodium bicarbonate solution. Thequenched mixture was partitioned between 300 ml of ether and 50 ml ofwater and the layers were separated. The organic layer was dried overmagnesium sulfate. The aqueous layer was extracted with 300 ml of ether;the extract was dried and combined with the original organic layer. Thecombined organics were concentrated in vacuo. Flash chromatography on150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded4.06 g (80%) of the title compound as a solid. ¹ H NMR (200 MHz ppm,CDCl₃) δ 2.50 (1H, dt, J=3.4, 12.0), 2.97 (1H, app d, J=12.0), 2.99 (1H,d, J=13.6), 3.72-3.79 (1H, m), 3.82 (1H, d, J=2.6), 4.00 (1H, d,J=13.6), 4.20 (dt, J=2.4, 11.6), 6.22 (1H, d, J=2.6), 7.22-7.37 (7H, m),7.57 (2H, appd, J=6.8), 8.07 (1H, s), 8.47 (2H, s). Anal. Calcd for C₂₆H₂₁ F₆ NO₃ : C, 61.29; H, 4.16; N, 2.75; F, 22.38. Found: C, 61.18; H,4.14; N, 2.70; F, 22.13.

DESCRIPTION 8

4-Benzyl-2-(R)-(1 -(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-phenylmorpholine

A solution of 2.50 g (4.9 mmol) of the compound of Description 7 and2.50 g (12.0 mmol) of dimethyl titanocene (Description 4a), in 35 ml of1:1 v/v THF/toluene was stirred in an oil bath at 80° C. for 16 hours.The reaction mixture was cooled and concentrated in vacuo. Flashchromatography on 150 g of silica gel using 3:1 v/v hexanes/methylenechloride as the eluant afforded 1.71 g (69%) of the title compound as asolid. ¹ H NMR (400 MHz, CDCl₃) δ 2.42 (1H, dt, J=3.6, 12.0), 2.89 (appd, J=11.6), 2.92 (1H, d, J=13.6), 3.61-3.66 (1H, m), 3.73 (1H, d,J=2.8), 4.00 (1H, d, J=13.6), 4.09 (1H, dt, J=2.4, 11.6), 4.75 (1H, d,J=2.8), 4.79 (1H, d, J=2.8), 5.36 (1H, d, J=2.4), 7.23-7.41 (7H, m),7.63 (1H, app d, J=7.2), 7.79 (1H, s), 7.91 (2H, s). MS (FAB) m/z 508(M+1, 25%). Anal. Calcd. for C₂₇ H₂₃ F₆ NO₂ : C, 63.90; H, 4.57; N,2.76; F, 22.46. Found: C, 63.71; H, 4.53; N, 2.68; F, 22.66.

DESCRIPTION 9

2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenylmorpholine

A mixture of the compound of Description 8 (1.5 g) and 10% palladium oncarbon catalyst (750 mg) in a mixture of isopropanol/ethyl acetate (25ml, 3:2 v/v) was stirred under an atmosphere of hydrogen for 48 h. Thecatalyst was removed by filtration through celite and the reaction flaskand filter pad were rinsed with ethyl acetate (500 ml). The filtrate wasconcentrated in vacuo, flash chromatography afforded epimer A (106 mg)and epimer B (899 mg) as clear oils. The title compound, epimer B hadthe following analysis: ¹ H NMR (CDCl₃, 400 MHz) δ 1.46 (3H, d, J=6.8Hz), 1.92 (1H, brs), 3.13 (1H, dd, J=3.0, 12.6 Hz), 3.24 (1H, dt, J=3.6,12.6 Hz), 3.62 (1H, dd, J=3.6, 11.2 Hz), 4.04 (1H, d, J=2.4 Hz), 4.14(1H, dt, J=3.0, 11.2 Hz), 4.48 (1H, d, J=2.4 Hz), 4.90 (1H, q, J=6.8Hz),7.21-7.32 (7H, m), 7.64 (1H, s). MS (CI⁺) m/z 420 (M⁺ +1, 20%), 178(100%). Anal. Calcd. for C₂₀ H₁₉ F₆ NO₂ : C, 57.28; H, 4.57; N, 3.34; F,27.18. Found: C, 57.41; H, 4.61; N, 3.29; F, 27.23.

EXAMPLE 1

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(4(dimethylaminomethyl)-1,2,5-oxadiazol-3-yl)methyl-3-(S)-phenylmorpholine

a) 3,4-Dimethyl-1,2,5-oxadiazole

A mixture of succinic anhydride (20 g) and dimethyl glyoxime (23.2 g)were heated in a 3-necked round bottom flask equipped with distillationapparatus. At 100° C. the reaction mixture liquified, and at 150° C. theproduct distilled. A second distillation yielded the product as acolourless liquid: bp 154°-159° C. ¹ H NMR (250 MHz,CDCl₃) δ 2.35 (6H,s).

b) 3-Chloromethyl-4-methyl-1,2,5-oxadiazole

α,α¹ -Azoisobutyronitrile (0.4 g) was added to the compound described in(a) (12.7 g) and sulfuryl chloride (10.41 ml) was added portionwise. Themixture was heated at 90° C. for 31/2 hours. Vacuum distillation (8 mmHg) yielded the product as a colourless liquid bp 60° C. (8 mm Hg). ¹ HNMR (250 MHz,CDCl₃) δ 2.48 (3H, s), 4.72 (2H, s).

c) 3,4-Bis(chloromethyl)-1,2,5-oxadiazole

α,α¹ -Azoisobutyronitrile (0.2 g) was added to the compound described in(b) (3.27 g) and sulfuryl chloride (2 ml) was added portionwise. Themixture was heated at 90° C. for 4 hours. The mixture was cooled,diluted with water (20 ml), and extracted with ether (3×10 ml). Thecombined organic phases were washed with brine (50 ml), dried (MgSO₄),and concentrated to leave a pale yellow oil, which was a mixture of thestarting material and product. ¹ H NMR signals for the product are asfollows: ¹ H NMR (250 MHz,CDCl₃) δ 2.48 (3H, s), 4.72 (2H, s), 4.85 (4H,s).

d)2-(R)-(1(R)-(3,5-Bis(tiifluoromethyl)phenyl)ethoxy)-4-(4-(dimethylaminomethyl)-1,2,5-oxadiazol-3-yl)methyl-3-(S)-phenylmorpholine

The compound of Description 9 (300 mg) in dimethylformamide (2 ml) wasadded slowly to a stirred mixture of the compound described in (c) (220mg) and potassium carbonate (273 mg) in dimethylformamide (2 ml) at roomtemperature. The mixture was then heated at 60° C. for 4 hours, and thencooled. Dimethylamine (2 ml) was added to the mixture, and stirred atroom temperature for 4 hours. The reaction mixture was diluted withwater (50 ml) and extracted with ethyl acetate (3×30 ml). The combinedorganic phases were washed with brine (1×50 ml), dried (MgSO₄), andconcentrated to leave an oil. This was purified by chromatography onsilica using ethyl acetate in hexane (1:4) as eluant to afford the titlecompound as an oil. ¹ H NMR (250 MHz,CDCl₃) δ 1.46 (3H, d, J=6.6 Hz),2.19 (6H, s), 2.68 (1H, td, J=3.3 Hz, 11.7 Hz), 2.88 (1H, d, J=11.8 Hz),3.38 (1H, d, J=14 Hz), 3.48 (1H, d, J=14.5 Hz), 3.49 (1H, d, J=2.8 Hz),3.60 (1H, d, J=14 Hz), 3.65 (1H, m), 3.87 (1H, d, J=14.5 Hz), 4.25 (1H,td, J=2.5 Hz, J=11.4 Hz), 4.36 (1H, d, J=3.6 Hz), 4.86 (1H, q, J=6.7Hz), 7.16 (2H, s), 7.33 (3H, m), 7.43 (2H, broad s), 7.61 (1H, s) MS(ES) m/z 559 (MH⁺).

EXAMPLE 2

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylaminomethyl)-1,2,5-oxadiazol-3-yl)methyl-3-(S)-(4-fluorophenyl)morpholine

This compound was prepared according to the procedure described inExample 1 using the compound of Description 5 as starting material.Purification by chromatography on silica using ethyl acetate in hexane(1:9, 1:3, then 1:1) as eluant afforded the title compound as acolourless oil. ¹ H NMR (360 MHz, DMSO) δ 1.39 (3H, d, J=6.6 Hz), 2.18(6H, s), 2.38 (1H, d, J=6.3 Hz) 2.52 (1H, td, J=3.4 Hz, 11.8 Hz), 2.83(1H, d, J=11.4 Hz), 3.30 (1H, d, J=8.4 Hz), 3.42 (2H, d, J=14.1 Hz),3.58 (1H, m), 3.78 (1H, d, J=14.7 hz), 4.13 (1H, t, J=9.2 Hz), 4.34 (1H,d, J=2.7 Hz), 4.96 (1H, d, J=6.6 Hz), 7.13 (2H, t, J=8.9 Hz), 7.42 (2H,s), 7.52 (2H, t, J=6.2 Hz), 7.86 (1H, s). MS (ES) m/z 577 (MH⁺).

EXAMPLE 3

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-piperidinomethyl-1,2,4-oxadiazol-5-yl)methylmorpholine

(a)2-(R)-(1-(R)-(3,5-Bistrifluoromethyl)phenyl)ethoxy)-4carbomethoxymethyl-3-(S)-phenylmorpholine

Methyl bromoacetate (0.15 ml) was added to a stirred mixture of thecompound of Description 9 (0.6 g) and potassium carbonate (0.52 g) indry dimethylformamide at 60° C. After 15 mins the reaction mixture wasdiluted with water (100 ml). The aqueous phase was washed with ethylacetate (3×25 ml). The combined organic phase was washed with brine,dried (MgSO₄) and concentrated to afford a clear oil. Purification wascarried out by chromatography on silica eluting with 20% ethyl acetatein petrol to afford a clear oil (0.592 g). ¹ H NMR (360 MHz,CDCl₃) δ1.46 (1H, d, J=10 Hz), 2.88-3.03 (2H, m), 3.08 (1H, d, J=12 Hz), 3.33(1H, d, J=12 Hz), 3.61 (3H, s), 3.62 (1H, m), 3.90 (1H, m), 4.28-4.42(2H, m), 4.86 (1H, q, J=10 Hz), 7.15 (2H, s), 7.26-7.42 (5H, m),7.60(1H, s). MS (CI⁺) m/z 492 (M+1⁺, 100%).

(b)2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-piperidinomethyl-1,2,4-oxadiazol-5-yl)methylmorpholine

Sodium hydride (0.057 g) and 2-(1-piperidino)acetamidoxime (0.188 g)were stirred together with molecular sieves and dry tetrahydrofuran for1/2 hr. A solution of the ester (Step a) in tetrahydrofuran was addeddropwise to this solution over 3 mins. The reaction was heated at refluxfor 1/2 hr. The molecular sieves were filtered and washed with ethylacetate. The filtrate was evaporated under reduced pressure and theresidue dispersed between water and ethyl acetate. The aqueous layer wasextracted with ethyl acetate (3×25 ml). The combined organics werewashed with brine, dried (MgSO₄) and evaporated under reduced pressureto afford a brown oil. Purification by chromatography on flash silicausing 50/50 ethyl acetate/petrol as eluant afforded the title compoundas a clear oil. ¹ H NMR (360 MHz,CDCl₃) δ 1.36-1.66 (9H, m), 2.43-2.54(4H, m), 2.68-2.82 (1H, m), 2.96-3.06 (1H, m), 3.60-3.76 (5H, m), 3.96(1H, d, J=2.2 Hz), 2.46-4.40 (2H, m), 4.82-4.90 (1H, q), 7.14 (2H, s),7.30-7.48 (5H, m), 7.60 (1H, s). MS CI⁺ m/z 599 (M+1⁺, 100%).

EXAMPLE 4

2-(R)-(1-(P)-(3,5-Bistrifluoromethyl)phenyl)ethoxy)-4-(3-(N,N-dimethylaminomethyl)-1,2,4-oxadiazol-5-yl)methyl-3-(S)-phenylmorpholine

(a) (N,N-Dimethylamino)acetamide oxime

Dimethylaminoacetonitrile (5 g) was dissolved in ethanol (12 ml).Hydroxylamine hydrochloride (4.13 g) was dissolved in water (5 ml) andadded to the reaction mixture over 3 min resulting in a slightlyexothermic reaction. The mixture was cooled and sodium carbonate wasadded portionwise and the reaction mixture was stirred for 1 hr. Themixture was filtered and concentrated in vacuo to afford a viscous whiteoil. This was crystallised from hot ethanol. (3.45 g): mp 135° C. ¹ HNMR (250 MHz,CDCl₃) δ 2.69 (6H, s), 3.60 (2H, s), 6.06 (2H, s).

(b)2-(R)-(1-(R)-(3,5-Bistrifluoromethyl)phenyl)ethoxy-4-(3-(N,N-dimethylaminomethyl)-1,2,4-oxadiazol-5-yl)methyl-3-(S)-phenylmorpholine

The compound of Example 3a was reacted with the product of step (a)above according to the procedure described for Example 3b to afford thetitle compound. (250 MHz,CDCl₃) δ 1.39 (3H, d, J=7 Hz), 2.29 (6H, s),2.58-2.72 (1H, m), 2.90-2.98 (1H, br d), 3.53-3.64 (5H, m), 3.85 (1H, d,J=15 Hz), 4.18-4.31 (1H, m), 4.74-4.85 (1H, q, J=7 Hz), 6.93-7.08 (4H,m), 7.32-7.42 (2H, m), 7.56 (1H, s). MS CI⁺ m/z 577 (M+1⁺, 100%).

We claim:
 1. A compound of the formula (I): ##STR13## wherein R¹represents hydrogen, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, C₁₋₆ alkoxy, C₁₋₄ alkylsubstituted by a hydroxy or C₁₋₄ alkoxy group, OCF₃, hydroxy,trifluoromethyl, trimethylsilyl, nitro, CN, SR^(a), SOR^(a), SO₂ R^(a),COR^(a), CO₂ R^(a) or CONR^(a) R^(b) where R^(a) and R^(b) are eachindependently hydrogen or C₁₋₄ alkyl;R² and R³ each independentlyrepresent hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by aC₁₋₄ alkoxy group, or trifluoromethyl; R⁴ represents hydrogen, halogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₁₋₆ alkoxy, C₁₋₄ alkyl substituted by a hydroxyor C₁₋₄ alkoxy group, OCF₃, hydroxy, trifluoromethyl, trimethylsilyl,nitro, CN, SR^(a), SOR^(a), SO₂ R^(a), COR^(a), CO₂ R^(a), CONR^(a)R^(b) where R^(a) and R^(b) are as previously defined; R⁵ representshydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by a C₁₋₄ alkoxygroup, or trifluoromethyl; R⁶ represents C₁₋₆ alkyl, optionallysubstituted by oxo, substituted by a 5-membered heteroaromatic ringselected from oxazole, thiazole, isoxazole, isothiazole, oxadiazole andthiadiazole, wherein each heteroaromatic ring is substituted at theavailable carbon atom by a group of the formula ZNR⁷ R⁸ where Z is C₁₋₆alkylene or C₃₋₆ cycloalkyl; R⁷ is hydrogen or C₁₋₄ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, or C₂₋₄ alkyl substituted by C₁₋₄alkoxy or hydroxyl; R⁸ is hydrogen or C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy, hydroxylor a 4, 5 or 6 membered heteroaliphatic ring containing one or twoheteroatoms selected from N, O and S; or R⁷, R⁸ and the nitrogen atom towhich they are attached form a heteroaliphatic ring of 4 to 7 ringatoms, optionally substituted by one or two groups selected from hydroxyor C₁₋₄ alkoxy optionally substituted by a C₁₋₄ alkoxy or hydroxylgroup, and optionally containing a double bond, which ring mayoptionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)₂or a second nitrogen atom which will be part of a NH or NRC moiety whereR^(c) is C₁₋₄ alkyl optionally substituted by hydroxy or C₁₋₄ alkoxy; orR⁷, R⁸ and the nitrogen atom to which they are attached form anon-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R⁷ andthe nitrogen atom to which they are attached form a heteroaliphatic ringto 4 to 7 ring atoms which may optionally contain an oxygen ring atom;R⁹ and R¹⁰ each independently represent hydrogen or C₁₋₄ alkyl, or R⁹and R¹⁰ are joined so, together with the carbon atoms to which they areattached, there is formed a C₅₋₇ ring; Y represents hydrogen or a C₁₋₄alkyl group optionally substituted by a hydroxy group; or apharmaceutically acceptable salt thereof.
 2. A compound as claimed inclaim 1 wherein R¹ is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or CF₃.3. A compound as claimed in claim 1 wherein R² is hydrogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, halogen or CF₃.
 4. A compound as claimed in claim 1 whereinR³ is hydrogen, fluorine, chlorine or CF₃.
 5. A compound as claimed inclaim 1 wherein R¹ and R² are in the 3 and 5 positions of the phenylring.
 6. A compound as claimed in claim 1 wherein R⁴ is hydrogen and R⁵is hydrogen or 4-fluoro.
 7. A compound as claimed in claim 1 wherein R⁹and R¹⁰ are each independently hydrogen or methyl.
 8. A compound asclaimed in claim 1 wherein R⁶ is C₁₋₆ alkyl substituted by a 5-memberedring selected from: ##STR14##
 9. A compound as claimed in claim 8wherein the 5-membered ring is selected from: ##STR15##
 10. A compoundas claimed in claim 1 wherein Z is CH₂ or CH₂ CH₂ and NR⁷ R⁸ is amino,methylamino, dimethylamino, diethylamino, azetidinyl, pyrrolidino andmorpholino.
 11. A compound of the formula (Ia): ##STR16## wherein R⁶ andY are as defined in claim 1 and A¹ is fluorine or CF₃ ;A² is fluorine orCF₃ ; and A³ is hydrogen or fluorine;or a pharmaceutically acceptablesalt thereof.
 12. A compound as claimed in claim 1 wherein Y is C₁₋₄alkyl optionally substituted by a hydroxy group.
 13. A compound selectedfrom:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylaminomethyl)-1,2,5-oxadiazol-3-yl)methyl-3-(S)-phenylmorpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylaminomethyl)-1,2,5-oxadiazol-3-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-piperidinomethyl)-1,2,4-oxadiazol-5-yl)methylmorpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-dimethylaminomethyl)-1,2,4-oxadiazol-5-yl)methyl-3-(S)-phenylmorpholine;ora pharmaceutically acceptable salt thereof.
 14. A compound as claimed inclaim 1 which has the stereochemistry of the 2- and 3-position that isshown in formula (Ib) ##STR17##
 15. A process for the preparation of acompound as claimed in claim 1, which comprises:(A), reacting a compoundof formula (II) ##STR18## wherein R¹, R², R³, R⁴, R⁵, R⁹, R¹⁰ and Y areas defined in claim 1 with a compound of formula (III):

    LG--R.sup.6a                                               (III)

where R^(6a) is a group of the formula R⁶ as defined in claim 1 or aprecursor therefor and LG is a leaving group such as an alkyl- orarylsulphonyloxy group or a halogen atom; and, if R^(6a) is a precursorgroup, converting it to a group R⁶ ; or (B), where R⁶ represents a C₁₋₆alkyl group substituted by a 1,2,4-oxadiazolyl or 1,2,4-thiadiazolylgroup, each of which heteroaromatic rings is substituted by ZNR⁷ R⁸, byreaction of a compound of formula (V): ##STR19## wherein m is an integerfrom 1 to 6, with a compound of formula (VI): ##STR20## in the presenceof a base; each process being followed, where necessary, by the removalof any protecting group where present; and when the compound of formula(I) is obtained as a mixture of enantiomers or diastereoisomers,optionally resolving the mixture to obtain the desired enantiomer;and/or, if desired, converting the resulting compound of formula (I) ora salt thereof, into a pharmaceutically acceptable salt thereof.
 16. Apharmaceutical composition comprising a compound as claimed in claim 1in association with a pharmaceutically acceptable carrier or excipient.17. A method for the treatment or prevention of physiological disordersassociated with an excess of tachykinins, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 18. A method according to claim 17 where thephysiological disorder is pain or inflammation.
 19. A method accordingto claim 17 where the physiological disorder is migraine.
 20. A methodaccording to claim 17 where the physiological disorder is emesis.
 21. Amethod according to claim 17 where the physiological disorder ispostherpetic neuralgia.